Metabolic responses and benefits of glucagon‐like peptide‐1 (GLP‐1) receptor ligands

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has undergone a revolutionary turnaround from discovery to clinically approved therapeutic. Rapid progress in drug design and formulation has led from initial development of short-and long-acting drugs suitable for daily or weekly parenteral administration, respectively, through to the most recent approval of an orally active GLP-1 agent. The current review outlines the biological action profile of GLP-1 including the various beneficial metabolic responses in pancreatic and extrapancreatic tissues, including the gastrointestinal tract, liver, bone and kidney as well as the reproductive cardiovascular and central nervous systems. We then briefly consider clinically approved GLP-1 receptor ligands and recent advances in this field. Given sustained evolution in the area of GLP-1 drug development and excellent safety profile, as well as the plethora of metabolic benefits, clinical approval for use in diseases beyond diabetes and obesity is very much conceivable.

Differential effects of RYGB surgery and best medical treatment for obesity-diabetes on intestinal and islet adaptations in obese-diabetic ZDSD rats

“…The morphological change was quantified using islet circularity index which suggested well-rounded islets in both experimental groups when compared to sham. Thus, in agreement with others, it is evident that RYGB, like GLP-1 therapy [ 64 – 68 ], restores islet morphology in rodents [ 20 , 31 , 32 ]. We also observed an increase in number of small islets and a corresponding decrease in large islets in all groups relative to SD rats.…”

Amplifying the antidiabetic actions of glucagon‐like peptide‐1: Potential benefits of new adjunct therapies

“…2,3 Moreover, these drugs have been shown to exert benefits across diverse organ systems, improving anti-inflammatory, bone, brain, cardiovascular, pancreatic, renal and reproductive functions. 3 Clinical uptake of GLP-1 receptor agonists was initially restricted by costs and requirement for injections; however, with patents set to expire giving rise to generic alternatives, as well advances in drug formulation allowing for oral delivery of GLP-1 receptor agonist, this versatile drug class should become accessible to many more patients. 3 Despite the success in treating diabetes, the clinical benefits of GLP-1 receptor agonists have yet to match the therapeutic advantages observed preclinically 4 or with bariatric surgery.…”

“…3 Clinical uptake of GLP-1 receptor agonists was initially restricted by costs and requirement for injections; however, with patents set to expire giving rise to generic alternatives, as well advances in drug formulation allowing for oral delivery of GLP-1 receptor agonist, this versatile drug class should become accessible to many more patients. 3 Despite the success in treating diabetes, the clinical benefits of GLP-1 receptor agonists have yet to match the therapeutic advantages observed preclinically 4 or with bariatric surgery. 5 This is partly attributed to dosedependent GIT side effects limiting the clinical application of these drugs, observations which were not fully apparent in preclinical studies.…”

“…In particular, the GIT hormone, glucagon‐like peptide‐1 (GLP‐1), is known to augment glucose‐stimulated insulin secretion, decrease glucagon secretion, improve beta‐cell proliferation and survival as well as preserve cell identity, delay gastric emptying and reduce appetite (Table 1). Collectively, these biological actions resulted in the independent approval of stable GLP‐1 receptor agonists for both type 2 diabetes and obesity 2,3 . Moreover, these drugs have been shown to exert benefits across diverse organ systems, improving anti‐inflammatory, bone, brain, cardiovascular, pancreatic, renal and reproductive functions 3 .…”

New developments in the prospects for GLP‐1 therapy

“…GLP-1 receptor agonists have been confirmed as a highly successful class of treatments for type 2 diabetes, but it has become apparent that there are many additional opportunities to broaden their therapeutic applications. These potential applications extend far beyond GLP-1's classic incretin effect and are reviewed here by Tanday et al (2021). Arguably, the largest scope for GLP-1R agonists is currently in the treatment of obesity.…”